S157: NILOTINIB VS. NILOTINIB + PEG-INTERFERON ΑLPHA INDUCTION AND NILOTINIB OR PEG-INTERFERON ΑLPHA MAINTENANCE THERAPY FOR NEWLY DIAGNOSED CHRONIC MYELOID LEUKEMIA PATIENTS. THE TIGER TRIAL.
Authors: Andreas Hochhaus, Andreas Burchert, Susanne Saußele, Gabriela M Baerlocher, Jiri Mayer, Tim H Brümmendorf, Paul La Rosee, Dominik Heim, Stefan W Krause, Philipp Le Coutre, Christian Fabisch, Jenny Rinke, Thoralf Lange, Alice Fabarius, Marcel Lorch, Mathias Hänel, Frank Stegelmann, Georg-Nikolaus Franke, Markus Radsak, Volker Kunzmann, Danny Himsel, Denise Kohn, Thomas Lang, Rüdiger Hehlmann, Thomas Ernst, Markus Pfirrmann
Journal: HemaSphere (2023)

Background: The TIGER-study (NCT01657604) is a multicenter, randomized phase III trial to evaluate efficacy and tolerability of nilotinib (NIL) monotherapy vs NIL+pegylated interferon α2b (IFN) combination therapy with IFN maintenance as first-line treatment for patients (pts) with chronic myeloid leukemia (CML) in chronic phase including success of treatment-free remission (TFR, Figure) Aims: The trial aims to improve treatment strategies in CML by improving induction and deescalating maintenance therapies using IFN as enhancer of immuno-surveillance. Methods: Between 2012 and 2017, 717 pts were recruited from 110 sites in Germany, Switzerland, and the Czech Republic. A pilot phase (n=25) validated the feasibility of the combination of NIL 300 mg BID and IFN (30-50μg/week according to tolerability and commenced after >≥6 weeks NIL monotherapy). During the main phase of the study, 692 pts were stratified according to the EUTOS score and randomized between NIL (n=353) and NIL/IFN combination (n=339) as induction therapies. Achievement of major molecular response (MMR, BCR::ABL1 transcripts ≤0.1% on the International Scale, IS) after >24 months (mo) therapy was the trigger for the start of the maintenance phase, TFR started in pts with ≥12 mo persistence of MR4 (BCR::ABL1 ≤0.01% IS) after >36 mo total therapy. Quality of life (QoL) was reported by pts using EORTC QLQ-C30 and CML24 questionnaires. Results: From 692 pts of the main phase, 411 were male (59%), median age at diagnosis was 51 years (range, 18-85), 13% were EUTOS high risk. Median observation time was 77 mo. 15 pts (2.2%) with atypical transcripts were not eligible for standardized molecular follow-up assessments. 571 pts concluded the induction phase. During maintenance phase, 345 pts (51%) showed sustained MR4 for ≥12 mo as trigger to stop therapy (NIL, n=192; NIL/IFN, n=153). Probabilities of MMR at 12 and 18 mo were 76% (95%-CI: 72-81%) and 81% (76-85%) with NIL and 83% (79-87%) and 88% (83-91%) with NIL/IFN, respectively (p=0.035 and 0.021). Probabilities of MR4 at 18 mo were 51% (46-57%) and 64% (58-69%) on NIL and NIL/IFN, respectively (p=0.0018). During IFN monotherapy, 18% experienced molecular recurrence (BCR::ABL1 >1% IS). From 345 pts in the discontinuation phase, probabilities of MMR at 12 and 24 mo were 60% (53-67%) and 48% (40-56%) in the NIL arm and 69% (60-76%) and 57% (48-65%) in the NIL/IFN arm, respectively (p=0.12 and p=0.13). 24 mo after treatment discontinuation, 22% and 22% of all randomized pts with typical transcripts were in TFR in the NIL and NIL/IFN arms, respectively (n.s.). Adverse events of special interest grade 3-5 were arteriovascular events in 9 vs 8%, fatigue in 2 vs 4%, thrombocytopenia in 8 vs 8%, and alanine aminotransferase elevation in 4 vs 9% of pts in the NIL vs NIL/IFN arms, respectively. QoL analyses revealed decreased cognitive function and higher rates of fatigue in male and female pts in the NIL/IFN arm particularly in pts >40 years. 20 pts progressed to advanced disease. By 8 years, progression-free survival was 94% (90-96%) and 92% (88-95%), overall survival 95% (92-97%) and 94% (91-97%) in the NIL and NIL/IFN arms, respectively (n.s.). 28 pts received an allogeneic stem cell transplantation, 14 after disease progression. 35 pts died, 9 related to CML. Summary/Conclusion: In the context of a well-controlled trial, survival of CML pts has reached probabilities close to normal. The combination of NIL with IFN is associated with a higher rate of molecular responses but also impaired tolerability. IFN maintenance is feasible, but did not result in a significantly improved chance of long-term TFR.Keywords: Tyrosine kinase inhibitor, Interferon alpha, Chronic myeloid leukemia, treatment-free remission